A modeling study to estimate prostate cancer-specific mortality on active surveillance for men with favorable intermediate-risk prostate cancer: Results from the SEARCH cohort.

PURPOSE: Limited data exist to help surgeons decide between active surveillance (AS) versus treatment for men with favorable intermediate risk (FIR) prostate cancer. To estimate the theoretical excess risk of prostate cancer-specific mortality (PCSM) with AS versus radical prostatectomy (RP), we determined the risk of PCSM in FIR men undergoing RP and modeled the PCSM risk for AS using a range of increased PSCM scenarios ranging from 1.25x to 2x higher relative to RP. MATERIALS AND METHODS: We retrospectively reviewed data from men undergoing RP from 1988 to 2017 at 8 Veterans Affairs hospitals within the SEARCH cohort. Men with FIR PC were identified using the NCCN risk criteria. Risk of PCSM at 5, 10, and 15 years after RP was estimated. Using these estimates, PCSM was then modeled for AS using a range of increased risk of PCSM relative to RP ranging from 1.25x to 2x higher. RESULTS: For the 920 FIR men identified, 5-, 10-, and 15-year survival estimates for PCSM after RP were 99.9%, 99.0%, and 97.8%, respectively. If the risk of PCSM on AS were 1.25-2x greater than RP, there would be 0.54%-2.17% excess risk of PCSM at 15 years. CONCLUSIONS: The risk of death for FIR after RP is very low. Assuming even modestly increased PCSM with AS versus RP, the excess risk of death for AS in FIR is low even up to 15 years. These data support the consideration of AS as a relatively safe alternative to RP in FIR men, though prospective randomized trials are needed to validate these findings.

Predictors of disparity between targeted and in-zone systematic cores during transrectal MR/US-fusion prostate biopsy.

BACKGROUND: The combination of targeted and systematic biopsies during MR/US-fusion prostate biopsy improves cancer detection over either modality alone. OBJECTIVE: To identify factors associated with disparity in detection of prostate cancer between systematic and targeted biopsies in magnetic resonance imaging positive zones. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively analyzed 171 men receiving initial MR/US fusion biopsy at our institution from 2015 to 2018. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Disparity was defined as positive targeted but negative systematic biopsy within an magnetic resonance imaging-positive zone (PIRADS 3+), or vice versa. Multivariable logistic regression was used to identify factors associated with disparity in detection of cancer on a per lesion basis. RESULTS AND LIMITATION: Three hundred and fifty-five lesions were targeted. For any cancer and clinically significant prostate cancer (csPCa), 37 (10%) and 24 (7%) lesions were target positive/systematic negative, respectively, while 30 (8%) and 23 (6%) lesions were target negative/systematic positive. In multivariable analysis, anterior location (OR 4.1, 95% CI 1.5-11.4, P = 0.007) was associated with csPCa target positive/systematic negative disparity, while higher prostate volume (OR 1.14, 95% CI 1.0-1.29, P = 0.04) was associated with csPCa target negative/systematic positive disparity. Shorter distance from apex (OR 1.02, 95% CI 1.01-1.04, P = 0.02) was associated with target positive/systematic negative disparity for any cancer. Limitations included relatively limited sample size and lack of prostatectomy specimen as a gold standard. CONCLUSIONS: Anterior or apical lesion location favors better disease capture on targeted biopsies. When doing systematic-only biopsies, surgeons may consider sampling the anterior zone separately.

Adverse Events Associated With Synthetic Male Slings: An Analysis of the Food and Drug Administration Manufacturer and User Facility Device Experience Database.

PURPOSE: We sought to describe and analyze the adverse events associated with synthetic male slings reported to the U.S. Food and Drug Administration (FDA) Manufacturer and User Facility Device Experience (MAUDE) database. METHODS: We queried the MAUDE database for all entries including the terms "Male Sling," "InVance," "Virtue," or "Advance" from January 1st, 2009 to December 31st, 2018. We collected and analyzed information about the event type, date received, report source, source type, and manufacturer. We reviewed and categorized the event description text for each medical device report (MDR). RESULTS: A total of 497 adverse events related to the male sling were identified. The adverse events were classified as injury (95.4%), malfunction (4.2%), and other (0.4%). There were no deaths described. The slings involved were the Advance or Advance XP sling (69.8%), InVance (15.5%), Virtue Quadratic (12.3%), or unknown (2.4%). The 4 most common adverse events described were urinary incontinence (46.7%), sling erosion (9.1%), mechanical malfunction (8.2%), and pain/numbness (8.2%). There was no increase in the number of reports in the years following the FDA warnings for urogynecologic mesh. CONCLUSION: There was an overall modest number of MDRs related to male slings and the majority of them were reported by the manufacturer. The reporting of adverse events for male slings does not seem to be affected by the controversy and scrutiny towards transvaginal mesh and midurethral slings. Further clinical studies and more objective and detailed databases are needed to investigate the safety of these synthetic slings.

Dutasteride Improves Nocturia but Does Not Lead to Better Sleep: Results from the REDUCE Clinical Trial.

PURPOSE: In men, complaints of nocturia causing poor sleep are often attributed to benign prostatic hyperplasia and treated with benign prostatic hyperplasia medications. We assessed whether treating lower urinary tract symptoms with dutasteride altered either nocturia or sleep quality using data from REDUCE. MATERIALS AND METHODS: REDUCE was a 4-year randomized, multicenter trial comparing dutasteride 0.5 mg/day vs placebo for prostate cancer chemoprevention. Study participants were men considered at increased risk for prostate cancer. Eligibility included age 50-75 years, prostate specific antigen 2.5-10 ng/ml, and 1 negative prostate biopsy. At baseline, 2 years and 4 years, men completed the International Prostate Symptom Score and Medical Outcomes Study Sleep Scale, a 6-item scale assessing sleep. To test differences in nocturia and Medical Outcomes Study Sleep Scale over time, we used linear mixed models adjusted for baseline confounders. Subanalyses were conducted in men symptomatic from lower urinary tract symptoms, nocturia, poor sleep, or combinations thereof. RESULTS: Of 6,914 men with complete baseline data, 80% and 59% were assessed at 2 and 4-year followup, respectively. Baseline characteristics were balanced between treatment arms. Dutasteride improved nocturia at 2 (-0.15, 95% CI -0.21, -0.09) and 4 years (-0.24, 95% CI -0.31, -0.18) but did not improve sleep. When limited to men symptomatic from lower urinary tract symptoms, nocturia, poor sleep or combinations thereof, results mirrored findings from the full cohort. CONCLUSIONS: In men with poor sleep who complain of nocturia, treatment of lower urinary tract symptoms with dutasteride modestly improves nocturia but has no effect on sleep. These results suggest men with poor sleep who complain of nocturia may not benefit from oral benign prostatic hyperplasia treatment.

Patient- and tumor-level risk factors for MRI-invisible prostate cancer.

BACKGROUND: Multiparametric MRI is highly sensitive for detection of clinically significant prostate cancer, but has a 10-20% false negative rate. It is unknown if there are clinical factors that predict MRI invisibility. We sought to identify predictors of MRI-invisible (MRI(-)) disease. METHODS: Men undergoing MRI/US-fusion targeted + systematic biopsy by two surgeons at our institution from 2015 to 2018 were reviewed. Patient demographics, clinical data, MRI metrics, and biopsy pathology results were obtained by chart review. An MRI(-) tumor was defined as a positive systematic biopsy in a zone without an MRI lesion. Factors associated with presence of MRI(-) tumors were identified using stepwise multivariable logistic regression. RESULTS: Of 194 men included in the analysis, 79 (41%) and 25 (13%) men had GG1+ and GG2+ MRI(-) tumors, respectively. On multivariable analysis, only Black race was associated with presence of GG1+ MRI(-) tumors (OR 2.2, 95% CI 1.02-4.96). Black race (OR 3.5, 95% CI 1.24-9.87) and higher PSA density (OR 2.0, 95% CI 1.34-3.20) were associated with presence of GG2+ MRI(-) tumors. In non-Black and Black men, detection of MRI(-) tumors on systematic biopsy upgraded patients from no disease to GG2+ disease 1% and 11% of the time, respectively, and from GG1 to GG2+ disease 42% and 60% of the time, respectively. CONCLUSIONS: Black race and PSA density were associated with presence of MRI(-) prostate cancer. Further study on racial differences is warranted based on these results. Surgeons should consider pre-biopsy risk factors before deciding to omit systematic prostate biopsy regardless of mpMRI results.

Risk Factors for Intraoperative Bladder Perforation at the Time of Midurethral Sling Placement.

OBJECTIVE: To evaluate patient-specific and perioperative factors that may be predictive of bladder perforation during midurethral sling placement. METHODS: A retrospective chart review of women who underwent a midurethral sling procedure at our institution between 2013 and 2017 was completed. All cases with bladder perforation were included. Patient demographics and perioperative factors were explored for associations with perforation. Bivariate analysis was used to compare baseline characteristics between those with and without perforation. Logistic regression modeling was used to identify predictors of perforation and associations between bladder perforation and postoperative sequelae. RESULTS: Four hundred and ten women had a urethral sling procedure at our institution between 2013 and 2017. Of these, 35 (9%) had evidence of bladder perforation on cystoscopy. This rate was higher for retropubic slings (15%) compared to transobturator slings (2%). Those with a perforation were younger (54 vs 61 years, P= .004) and had a lower average BMI (24.1 kg/m2 vs 26.3 kg/m2, P = .022). Other risk factors included lack of pre-existing apical prolapse (11% vs 4%, P = .012) and concomitant urethrolysis (27% vs 8%, P = .024). In multivariable analysis, age, BMI, and sling type were significantly associated with perforation. In univariate analysis, perforation was associated with postoperative lower urinary tract symptoms (OR 2.3, P = .21) and urinary tract infection within 30 days of surgery (OR 2.2, P = .047). CONCLUSIONS: Intraoperative bladder perforation was associated with younger patient age and lower BMI. Additionally, bladder perforation is a risk factor for postoperative urinary tract infection and lower urinary tract symptoms.

Economic evaluation of elective cesarean versus vaginal delivery on cost of future pelvic floor disorders in the United States.

AIM: To analyze the cost impact of cesarean versus vaginal delivery in the United States on the development of stress urinary incontinence (SUI) and pelvic organ prolapse (POP). METHODS: We compared average cost of delivery method to the lifetime risk and cost of pelvic floor disorders (PFDs) in women < 65 years. Costs of maternal care, obtained from the MarketScan® database, included those incurred at delivery and 3 months post-partum. Future costs of PFDs included those incurred after delivery up to 65 years. Previously reported data on the prevalence of POP and SUI following cesarean and vaginal delivery was used to calculate attributable risk. An incremental cost of illness model was used to estimate costs for SUI. Direct surgical and ambulatory care costs were used to determine cost of POP. RESULTS: Average estimated cost was $7089 for vaginal delivery and $9905 for cesarean delivery. The absolute risks for SUI and POP were estimated as 7% and 5%, respectively, following cesarean delivery, and 13% and 14%, respectively, following vaginal delivery. For SUI, average direct cost was $5642, indirect cost was $4208, and personal cost was $750. Average direct cost of POP surgery was $4658, and nonsurgical cost was $2220. The potential savings for reduced prevalence of SUI and POP in women who underwent cesarean delivery is estimated at $1255, but they incur an additional $2816 maternal care cost over vaginal delivery. CONCLUSIONS: Although elective cesarean is associated with reduced prevalence of PFDs, the increased initial cost of cesarean delivery does not offset future cost savings.

Multiple modes of Lrp4 function in modulation of Wnt/ß-catenin signaling during tooth development.

During development and homeostasis, precise control of Wnt/ß-catenin signaling is in part achieved by secreted and membrane proteins that negatively control activity of the Wnt co-receptors Lrp5 and Lrp6. Lrp4 is related to Lrp5/6 and is implicated in modulation of Wnt/ß-catenin signaling, presumably through its ability to bind to the Wise (Sostdc1)/sclerostin (Sost) family of Wnt antagonists. To gain insights into the molecular mechanisms of Lrp4 function in modulating Wnt signaling, we performed an array of genetic analyses in murine tooth development, where Lrp4 and Wise play important roles. We provide genetic evidence that Lrp4 mediates the Wnt inhibitory function of Wise and also modulates Wnt/ß-catenin signaling independently of Wise. Chimeric receptor analyses raise the possibility that the Lrp4 extracellular domain interacts with Wnt ligands, as well as the Wnt antagonists. Diverse modes of Lrp4 function are supported by severe tooth phenotypes of mice carrying a human mutation known to abolish Lrp4 binding to Sost. Our data suggest a model whereby Lrp4 modulates Wnt/ß-catenin signaling via interaction with Wnt ligands and antagonists in a context-dependent manner.

Collagenase Clostridium histolyticum in the treatment of Peyronie's disease: patient selection and perspectives.

The safety and efficacy of the use of collagenase Clostridium histolyticum (CCH) for the treatment of Peyronie's disease has been confirmed over the past several years. However, identification of the ideal patient population for use of this treatment is not well established. Multiple studies have attempted to delineate various patient-specific factors that may predict response to treatment with CCH, with the intent of enhancing patient selection. To date, these include baseline curvature severity, duration of disease, disease phase at presentation, plaque calcification, baseline erectile function, plaque size, age, comorbid diabetes, previous penile trauma, responsiveness to first treatment cycle, baseline penile shortening or pain, prior treatment with intralesional injection, compliance with plaque modeling, and atypical curvature. In addition, other studies have sought to explore various aspects of treatment with CCH that may affect patient perspective of treatment. They have focused on patient-reported outcomes, female partner considerations, cost of treatment, and potential confounders of patient satisfaction. This review provides a summary and analysis of currently available literature on topics of patient selection and perspectives in regard to treatment of Peyronie's disease with CCH.

Muscle satellite cell proliferation and association: new insights from myofiber time-lapse imaging.

BACKGROUND: As the resident stem cells of skeletal muscle, satellite cells are activated by extracellular cues associated with local damage. Once activated, satellite cells will re-enter the cell cycle to proliferate and supply a population of myoblasts, which will repair or replace damaged myofibers by differentiating and fusing either with an existing myofiber or with each other. There is also evidence that the orientation of cell division with respect to the myofiber may indicate or convey asymmetry in the two daughter cells. Our recent studies with time-lapse imaging of myofiber-associated satellite cells in vitro have yielded new data on the timing and orientation of satellite cell divisions, and revealed persistent differences in the behavior of daughter cells from planar versus vertical divisions. RESULTS: We analyzed 244 individual fiber-associated satellite cells in time-lapse video from 24 to 48 hours after myofiber harvest. We found that initial cell division in fiber culture is not synchronous, although presumably all cells were activated by the initial trauma of harvest; that cell cycling time is significantly shorter than previously thought (as short as 4.8 hours, averaging 10 hours between the first and second divisions and eight hours between the second and third); and that timing of subsequent divisions is not strongly correlated with timing of the initial division. Approximately 65% of first and 80% of second cell divisions occur parallel to the axis of the myofiber, whereas the remainder occur outside the plane of the fiber surface (vertical division). We previously demonstrated that daughter cells frequently remain associated with each other after division or reassociate after a brief separation, and that unrelated cells may also associate for significant periods of time. We show in this paper that daughter cells resulting from a vertical division remain associated with one another several times longer than do daughters from a horizontal division. However, the total average time of association between sister cells is not significantly different from the total average time of association between unrelated cells. CONCLUSIONS: These longitudinal characterizations of satellite cell behavior shortly after activation provide new insights into cell proliferation and association as a function of relatedness, and indicate significant and consistent heterogeneity within the population based on these metrics.